Treatment or prevention of cardiovascular events via the administration of a colchicine derivative

ABSTRACT

A method for the treatment or prevention of a cardiovascular event in a subject with atherosclerotic vascular disease comprising the step of:
         b) administering a therapeutically effective amount of a compound of formula (I), a known colchicine derivative and/or a salt thereof       

     
       
         
         
             
             
         
       
     
     wherein:
     R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R 11  and R 12  independently represent hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 3-6  cycloalkyl, halogen, C 1-4  haloalkyl, nitro, amino, C 2-4  acylamino, C 1-4  alkyl or dialkylamino, hydroxyl, C 1-4  alkoxy, C 1-4  alkylthio, a group of the formula —SO 2 N(R) 2  or SO 2 R x  where R x  is C 1-4  alkyl, C 1-4  acyloxy, or optionally substituted phenyl, optionally substituted phenoxy;   R 7  and R 8  independently represent hydrogen, C 1-4  alkyl or C 1-4  acyl; and   R 5 ′, R 5 ″, R 6 ′ and R 6 ″ independently represent hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 3-6  cycloalkyl, halogen, C 1-4  haloalkyl, nitro, amino, C 2-4  acylamino, hydroxyl, C 1-4  alkoxy or C 1-4  alkylthio a group of the formula —SO 2 N(R x ) 2  or SO 2 R x  where R x  is C 1-4  alkyl,   C 1-4  acyloxy, or optionally substituted phenyl.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/390,606, filed Apr. 22, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/440,147, filed May 1, 2015, which is a NationalStage Entry of PCT Application No. PCT/AU2013/001261, filed Nov. 1,2013, which claims the benefit of AU2012/904868, filed Nov. 5, 2012 andAU2012/904828, filed Nov. 2, 2012, the entire contents of which areincorporated herein by reference.

TECHNICAL FIELD

A method for the treatment and/or prevention of cardiovascular events inpatients with established atherosclerotic vascular disease.

BACKGROUND ART

The following discussion of the background art is intended to facilitatean understanding of the present invention only. The discussion is not anacknowledgement or admission that any of the material referred to is orwas part of the common general knowledge as at the priority date of theapplication.

In patients with atherosclerotic vascular disease, the diseased vesselwall is subject to injurious forces that promote plaque build-up andinstability that may lead to coronary occlusion resulting in heartattack, ischemic stroke and sudden death.

The response to injury within the diseased vessel is dependent on thearchitecture and content of atherosclerotic plaques. Lipid-rich plaqueswith a neo-vascular base are particularly susceptible to the effect ofinjury, which may leave them vulnerable to neutrophil infiltration.Neutrophils that enter the interstitial space may become activated uponexposure to the plaque contents, inciting an aggressive inflammatoryresponse that may accelerate plaque instability increasing the risk ofplaque enlargement and rupture and hence increasing the risk of clinicalevents.

Despite routine use of anti-platelet and statin therapy, patients withatherosclerotic vascular disease continue to be at risk ofcardiovascular events, possibly because these treatments fail to targetsome of the inflammatory pathways implicated in the disease.

A number of additional treatments exist for the prevention or reductionin risk of coronary heart disease, including: antiplatelet agents(besides aspirin), anticoagulants, angiotensin-converting-enzymeinhibitors (ACEIs); aldosterone receptor antagonists (ARAs);beta-blockers calcium channel blockers and/or nitrates.

However, many of these treatments are recommended for acute conditionsand do not address or provide for a long-term reduction incardiovascular events in patients with clinically stable atheroscleroticvascular disease.

It is against this background that the present invention has beendeveloped.

The present invention seeks to overcome, or at least ameliorate, one ormore of the deficiencies of the prior art mentioned above, or to providethe consumer with a useful or commercial choice.

SUMMARY OF INVENTION

The present invention provides a method for the treatment or preventionof a cardiovascular event in a subject comprising the step of:

-   -   administering a therapeutically effective amount of a compound        of formula (I), a known colchicine derivative and/or a salt        thereof.

The present invention provides a method for the treatment or preventionof a cardiovascular event in a subject with atherosclerotic vasculardisease comprising the step of: administering a therapeuticallyeffective amount of a compound of formula (I), a known colchicinederivative and/or a salt thereof.

The present invention further provides a method for the treatment orprevention of a cardiovascular event in a subject with atheroscleroticvascular disease comprising the step of:

-   -   administering a therapeutically effective amount of a compound        of formula (I), a known colchicine derivative and/or a salt        thereof and one or more additional agents selected from the list        comprising: a statin and/or an anti-platelet agent.

Preferably the atherosclerotic vascular disease is a coronary disease.The coronary disease may be stable or unstable.

The invention further provides a method for the treatment or preventionof a cardiovascular event in a subject comprising the step of:

-   -   administering a therapeutically effective amount of a compound        of formula (I), a known colchicine derivative and/or a salt        thereof        wherein the subject has coronary disease prior to administration        of the therapeutically effective amount of a compound of formula        (I), a known colchicine derivative and/or a salt thereof.        Preferably the coronary disease is a stable coronary disease.

The present invention provides a method for reducing or preventingcholesterol crystal induced inflammation within atherosclerotic plaquesin a subject, comprising the step of

-   -   administering a dosage of 0.5 mg or 0.6 mg of a compound of        formula (I), a known colchicine derivative and/or a salt        thereof.

The invention also provides for the use of a compound of formula (I), aknown colchicine derivative and/or a salt thereof in the preparation ofa medicament for the treatment or prevention of a cardiovascular event.

In addition, the invention provides a composition for the prevention ortreatment of a cardiovascular event in a subject, the compositioncomprising a therapeutically effective amount of a compound of formula(I), a known colchicine derivative and/or a salt thereof and one or morepharmaceutically acceptable additives, excipients carriers and/ordiluents.

Preferably, the composition comprises 0.5 mg or 0.6 mg of a compound offormula (I), a known colchicine derivative and/or a salt thereof.

Preferably, the composition further comprises one or more additionalagents selected from the list comprising: a statin and/or ananti-platelet agent.

The present invention provides a regimen for the treatment or preventionof a cardiovascular event in a subject, the regimen comprising the stepof:

-   -   administering a dosage of 0.5 mg or 0.6 mg of a compound of        formula (I), a known colchicine derivative and/or a salt thereof        once per day.

The present invention also provides a regimen for reducing or preventingcholesterol crystal induced inflammation within atherosclerotic plaquesin a subject, the regimen comprising the step of:

-   -   administering a dosage of 0.5 mg or 0.6 mg of a compound of        formula (I), a known colchicine derivative and/or a salt thereof        once or more times per day.

Preferably, the subject being administered the regimen hasatherosclerotic vascular disease, more preferably a coronary diseasewhich may be a stable or unstable coronary disease.

FIGURES

FIG. 1 is a flow chart of the subject enrolment process for Example 1.

FIG. 2 is a graph of the time to first clinical event in each group bytreatment.

FIG. 3 is a table of the first time to clinical event across subgroupsexamined.

FIG. 4 is series of graphs of the time to first clinical event in eachgroup by treatment broken down into specific events.

DETAILED DESCRIPTION OF THE INVENTION General

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. The invention includes all such variation andmodifications. The invention also includes all of the steps, features,formulations and compounds referred to or indicated in thespecification, individually or collectively and any and all combinationsor any two or more of the steps or features.

Each document, reference, patent application or patent cited in thistext is expressly incorporated herein in their entirety by reference,which means that it should be read and considered by the reader as partof this text. That the document, reference, patent application or patentcited in this text is not repeated in this text is merely for reasons ofconciseness. Any manufacturer's instructions, descriptions, productspecifications, and product sheets for any products mentioned herein orin any document incorporated by reference herein, are herebyincorporated herein by reference, and may be employed in the practice ofthe invention. No admission is made that any of the referencesconstitute prior art or are part of the common general knowledge ofthose working in the field to which this invention relates.

The present invention is not to be limited in scope by any of thespecific embodiments described herein. These embodiments are intendedfor the purpose of exemplification only. Functionally equivalentproducts, formulations and methods are clearly within the scope of theinvention as described herein.

The invention described herein may include one or more range of values(eg. size, displacement and field strength etc). A range of values willbe understood to include all values within the range, including thevalues defining the range, and values adjacent to the range which leadto the same or substantially the same outcome as the values immediatelyadjacent to that value which defines the boundary to the range.

Other definitions for selected terms used herein may be found within thedetailed description of the invention and apply throughout. Unlessotherwise defined, all other scientific and technical terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which the invention belongs. The term “active agent” may meanone active agent, or may encompass two or more active agents.

Throughout this specification, unless the context requires otherwise,the word “comprise” or variations such as “comprises” or “comprising”,will be understood to imply the inclusion of a stated integer or groupof integers but not the exclusion of any other integer or group ofintegers.

DETAILED DESCRIPTION

It is well known that consumption of a range of non-steroidalanti-inflammatory agents, such as Vioxx® (rofecoxib), Celebrex®(celecoxib), ibuprofen, Voltaren® (diclofenac), by patients with aprevious history of coronary heart disease or other atheroscleroticvascular disease may lead to a significant increase in the risk offurther cardiovascular events such as myocardial infarction. Otheranti-inflammatory agents such as cortisone can also increase the risk ofadverse effects and cardiovascular events in patients with a previoushistory of coronary heart disease. Despite the anti-inflammatory effectsof these agents and their ability to reduce the markers of inflammation(such as a reduction in the levels of c-reactive protein), they arecontra-indicated in the treatment of patients with coronary heartdisease or other atherosclerotic vascular disease.

In atherosclerotic vascular disease, an artery wall thickens as a resultof the accumulation of calcium and fatty materials such as cholesterol.It is a syndrome affecting arterial blood vessels, a chronicinflammatory response in the walls of arteries specifically due toatheromatous plaques. Disruption of the plaques may lead to acutecoronary syndrome (including ischemic chest pain, acute myocardialinfarction, unstable angina); cardiac arrest; and/or stroke such asnon-cardio-embolic ischemic stroke.

Coronary disease and coronary heart disease is a form of atheroscleroticvascular disease caused by plaque building up along the inner walls ofthe arteries of the heart, which narrows the arteries and reduces bloodflow to the heart. Stable coronary diseases are those that occurpredictably in intensity, character or frequency at known levels ofexertion or other stimuli. Unstable coronary diseases are those thatchange in intensity, character or frequency.

The inventors of the present invention have surprisingly found thatadministration of an anti-inflammatory agent within the group ofcompounds defined by formula (I) may treat or prevent cardiovascularevents in patients with atherosclerotic vascular disease such ascoronary heart disease.

wherein:R₁, R₂, R₃, R₄, R₉, R₁₀, R₁₁ and R₁₂ independently represent hydrogen,C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkyl,nitro, amino, C₂₋₄ acylamino, C₁₋₄ alkyl or dialkylamino, hydroxyl, C₁₋₄alkoxy, C₁₋₄ alkylthio, a group of the formula —SO₂N(R)₂ or SO₂R^(x)where R^(x) is C₁₋₄ alkyl, C₁₋₄ acyloxy, or optionally substitutedphenyl, optionally substituted phenoxy;R₇ and R₈ independently represent hydrogen, C₁₋₄ alkyl or C₁₋₄ acyl; andR₅′, R₅″, R₆′ and R₆″ independently represent hydrogen, C₁₋₄ alkyl, C₂₋₄alkenyl, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkyl, nitro, amino, C₂₋₄acylamino, hydroxyl, C₁₋₄ alkoxy or C₁₋₄ alkylthio a group of theformula —SO₂N(R^(x))₂ or SO₂R^(x) where R^(x) is C₁₋₄ alkyl, C₁₋₄acyloxy, or optionally substituted phenyl.

In particular, the inventors have discovered that colchicine[N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[α]heptalen-7-yl]acetamide]may treat or prevent cardiovascular events in patients withatherosclerotic vascular disease such as coronary heart disease.

Certain compounds of formula (I), and methods for their synthesis aredescribed in the following publications, the contents of which areincorporated by reference:

-   Kouroupis, Pavlos; Hansen, Hans-Jurgen, From Colchicine and Some of    Its Derivatives to 1,2,3,9,10-Pentamethoxybenzo[α]heptalenes,    Helvetica Chimica Acta; Vol. 78; (1995); p. 1247-1277.-   Sun, Li; McPhail, Andrew T.; Hamel, Ernest; Lin, Chii M.; Hastie,    Susan B.; et al. Antitumor Agents. 139. Synthesis and Biological    Evaluation of Thiocolchicine Analogs 5,6-Dihydro-6(S)-(acyloxy)- and    5,6-Dihydro-6(S)-(aroyloxy)methyl-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[α]naphthalen-8-ones    as Novel Cytotoxic and Antimitotic Agents, Journal of Medicinal    Chemistry; Vol. 36(5); (1993); p. 544-551-   Kouroupis, Pavlos; Kessler, Jacqueline; Hansen, Hans-Juergen,    10-Alkyl-10-demethylcolchicines, Helvetica Chimica Acta; Vol. 79;    (1996); p. 208-212.-   Chang, Dong-Jo; Jung, Jong-Wha; An, Hongchan; Suh, Young-Ger; Yoon,    Eun-Young; Lee, Geon-Bong; Kim, Soon-Ok; Kim, Wan-Joo; Kim,    Young-Myeon, Design, synthesis and identification of novel    colchicine-derived immunosuppressant, Bioorganic and Medicinal    Chemistry Letters; Vol. 19(15); (2009); p. 4416-4420.-   Kozaka, Takashi; Nakagawa-Goto, Kyoko; Shi, Qian; Lai, Chin-Yu;    Brossi, Arnold; Lee, Kuo-Hsiung; Hamel, Ernest; Bastow, Kenneth F.,    Antitumor agents 273. 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Toxicity    Quantitative Structure-Activity Relationships of Colchicines Journal    of Medicinal Chemistry; Vol. 24(5); (1981); p. 636-639-   Bensel, Nicolas; Lagnoux, David; Niggli, Verena; Wartmann, Markus;    Reymond, Jean-Louis New C(4)-Functionalized Colchicine Derivatives    by a Versatile Multicomponent Electrophilic Aromatic Substitution    Helvetica Chimica Acta; Vol. 87(9); (2004); p. 2266-2272-   Malysheva, Yulia B.; Fedorov, Alexey Yu.; Combes, Sebastien;    Allegro, Diane; Peyrot, Vincent; Knochel, Paul; Gavryushin, Andrei    E., Synthesis and biological evaluation of novel anticancer bivalent    colchicine-tubulizine hybrids Bioorganic and Medicinal Chemistry;    Vol. 20(14); (2012); p. 4271-4278.-   Kouroupis, Pavlos; Linden, Anthony; Hansen, Hans-Juergen, Synthesis    of 4-Acetylcolchicine Helvetica, Chimica Acta; Vol. 79, (1996); p.    203-207-   Bensel, Nicolas; Lagnoux, David; Niggli, Verena; Wartmann, Markus;    Reymond, Jean-Louis New C(4)-Functionalized Colchicine Derivatives    by a Versatile Multicomponent Electrophilic Aromatic Substitution    Helvetica Chimica Acta; Vol. 87(9); (2004); p. 2266-2272.-   Chang, Dong-Jo; Jung, Jong-Wha; An, Hongchan; Suh, Young-Ger; Yoon,    Eun-Young; Lee, Geon-Bong; Kim, Soon-Ok; Kim, Wan-Joo; Kim,    Young-Myeon, Design, synthesis and identification of novel    colchicine-derived immunosuppressant, Bioorganic and Medicinal    Chemistry Letters; vol. 19; nb. 15; (2009); p. 4416-4420.-   Hufford, Charles D.; Capraro, Hans-Georg; Brossi, Arnold. (13)C- and    (1)HNMR. Assignments for Colchicine Derivatives, Helvetica Chimica    Acta; Vol. 63(1); (1980); p. 50-56.-   Nicolaou, K. C.; Valiulin, Roman A.; Pokorski, Jonathan K.; Chang,    Vicki; Chen, Jason S., Bio-inspired synthesis and biological    evaluation of a colchicine-related compound library, Bioorganic and    Medicinal Chemistry Letters; vol. 22; nb. 11; (2012); p. 3776-3780.-   Patil, Shivaputra A.; Wang, Jin; Li, Xiaochen S.; Chen, Jianjun;    Hosni-Ahmed, Amira; Patil, Renukadevi; Li, Wei; Miller, Duane D.;    Jones, Terreia S.; Seibel, William L. New substituted 4H-chromenes    as anticancer agents Bioorganic and Medicinal Chemistry Letters;    vol. 22; nb. 13; (2012); p. 4458-446.-   Nielsen, Kurt; Manchanda, Rajesh Deuterium-enriched colchicines,    Thiocolchicine and derivatives thereof; Methods of preparation and    use thereof, Patent: US2011/178180; (2011); (A1).-   Bartusik, Dorota; Tomanek, Boguslaw; Fallone, Gino; Lattova, Erika;    Perreault, Helene; Tuszynski, Jack, Derivatives of thiocolchicine    and its applications to CEM cells treatment using 19F Magnetic    Resonance ex vivo Bioorganic Chemistry; vol. 38; nb. 1; (2010); p.    1-6.-   Alali, Feras Q.; Qandil, Amjad; Gharaibeh, Ahmad A.; Ghawanmeh,    Abdullah; Tawaha, Khaled; Burgess, Jason P.; Sy, Arlene; Nakanishi,    Yuka; Kroll, David J.; Oberlies, Nicholas H. Colchicinoids from    Colchicum crocifolium Boiss. (Colchicaceae) Natural Product    Research; vol. 24(2); (2010); p. 152-159.-   Boyer, Franois-Didier; Dubois, Joelle; Thoret, Sylviane; Dau,    Marie-Elise Tran Huu; Hanna, Issam, Synthesis and tubulin-binding    properties of new allocolchicinoids Bioorganic Chemistry; vol.    38(4); (2010); p. 149-158.-   Yang, Baiyuan; Zhu, Zhiqing C.; Goodson, Holly V.; Miller, Marvin J.    Syntheses and biological evaluation of ring-C modified colchicine    analogs, Bioorganic and Medicinal Chemistry Letters; Vol. 20(12);    (2010); p. 3831-3833.-   Stefely, Jonathan A.; Miller, Patricia A.; Peterson, Rebecca J.;    Moraski, Garrett C.; Miller, Marvin J.; Palchaudhuri, Rahul;    Hergenrother, Paul J.,    N-((1-benzyl-1H-1,2,3-triazol-4-yOmethyOarylamide as a new scaffold    that provides rapid access to antimicrotubule agents: synthesis and    evaluation of antiproliferative activity against select cancer cell    lines, Journal of Medicinal Chemistry; Vol. 53(8); (2010); p.    3389-3395.-   Kozaka, Takashi; Nakagawa-Goto, Kyoko; Shi, Qian; Lai, Chin-Yu;    Brossi, Arnold; Lee, Kuo-Hsiung; Hamel, Ernest; Bastow, Kenneth F.    Antitumor agents 273. Design and synthesis of    N-alkyl-thiocolchicinoids as potential antitumor agents, Bioorganic    and Medicinal Chemistry Letters; Vol. 20.(14); (2010); p. 4091-4094.-   Johansson, Emma M. V.; Darbre, Tamis; Reymond, Jean-Louis; Dubois,    Joelle, Glycopeptide dendrimer colchicine conjugates targeting    cancer cells, Bioorganic and Medicinal Chemistry; Vol. 18(17);    (2010); p. 6589-6597.-   Dietrich, Andrea; Mueller, Thomas; Schobert, Rainer; Biersack,    Bernhard; Effenberger, Katharina; Knauer, Sebastian;    4-(3-Halo/amino-4,5-dimethoxyphenyI)-5-atyloxazoles and    —N-methylimidazoles that are cytotoxic against combretastatin a    resistant tumor cells and vascular disrupting in a cisplatin    resistant germ cell tumor model Journal of Medicinal Chemistry, Vol.    53(18); (2010); p. 6595-6602.-   Nicolaus, Norman; Neudoerfl, Joerg-Martin; Schmalz, Hans-Guenther;    Zapke, Janet; Oschkinat, Hartmut; Riesterer, Philipp; Prokop, Aram,    Azides derived from colchicine and their use in library synthesis: A    practical entry to new bioactive derivatives of an old natural drug,    ChemMedChem; vol. 5(5) (2010); p. 661-665.-   Sharma, Shubhada; Ravindra, Rudravajhala; Blanden, Adam R.; Bane,    Susan; Poliks, Barbara; Chiauzzi, Colby Characterization of the    colchicine binding site on avian tubulin isotype 131/I,    Biochemistry; vol. 49(13); (2010); p. 2932-2942.-   Indena S.p.A. “Process for the glycosidation of colchicine and    thiocolchicine” Patent: EP2128170; (2009); (A1).-   Sun, Tong; Nielsen, Kurt; Watson, Shawn; Hilfiker, Rolf; Sieber,    Andreas, Colchicine Solid-State forms: Methods of Making and Methods    of Use Thereof, Patent: US2009/312430; (2009); (A1).-   Bartusik, Dorota; Tomanek, Boguslaw; Fallone, Gino; Lattova, Erika;    Perreault, Helene; Tuszynski, Jack The efficacy of new colchicine    derivatives and viability of the TLymphoblastoid cells in    three-dimensional culture using 19F MRI and HPLCUV ex vivo,    Bioorganic Chemistry; vol. 37(6); (2009); p. 193-201.-   Chang, Dong-Jo; Jung, Jong-Who; An, Hongchan; Suh, Young-Ger; Yoon,    Eun-Young; Lee, Geon-Bong; Kim, Soon-Ok; Kim, Wan-Joo; Kim, Young    Myeong, Design, synthesis and identification of novel    colchicine-derived immunosuppressant, Bioorganic and Medicinal    Chemistry Letters; vol. 19(15); (2009); p. 4416-4420.-   ALBERTA HEALTH SERVICES; Novel Colchicine Derivatives, Methods and    Uses Thereof, Patent: W02011/22805; (2011); (A1)-   MUTUAL PHARMACEUTICAL COMPANY, INC.; MANCHANDA, Rajesh,    Thiocolchicine Derivatives, method of making and method of use    thereof, Patent: W02010/138670; (2010); (A2)

These publications disclose a large number of compounds derived fromcolchicine, not all of which fall within the scope of formula (I).Compounds outside the scope of formula (I), yet derived from colchicineand described in the aforementioned publications, are collectivelyreferred to herein as “known colchicine derivatives”.

The compounds of formula (I) and the known colchicine derivativescontain at least one asymmetric carbon atom. The methods of the presentinvention include the use of isolated optical isomers and/or mixtures ofsuch.

The term C1-4 alkyl as used herein means a straight or branched chainalkyl group containing from 1 to 4 carbon atoms, i.e. methyl, ethyl,isopropyl, n-propyl, sbutyl, isobutyl and n-butyl.

The term C1-4 haloalkyl means the abovementioned alkyl groupssubstituted by one or more halogen atoms, e.g. trifluoromethyl.

The term C1-4 alkoxy and C1-4 alkylthio refer to the abovementionedalkyl groups attached through an oxygen or sulphur atom respectively tothe relevant ring.

The term C2-4 alkenyl refers to groups such as vinyl, allyl and butenyl.

The term amino indicates a group of formula —NH2 and also substitutedamino groups such as mono-C1-4 alkylamino and di-C1-4 alkyl aminogroups.

The term C2-4 acyl amino means an amino group substituted by a C2-4 acylgroup such as acetyl.

The term C1-4 alkanoyl refers to groups such as formyl or acetyl.

The term C3-8 cycloalkyl means a saturated ring having from 3 to 8carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cyclooctyl.

The term optionally substituted phenyl as used herein means a phenylgroup unsubstituted or substituted by one or more groups such ashalogen, trifluoromethyl, methyl, methoxy or nitro.

The term optionally substituted phenoxy as used herein means a phenoxygroup unsubstituted or substituted by one or more groups such ashalogen, trifluoromethyl, methyl, methoxy or nitro.

Therefore, the present invention provides a method for the prevention ortreatment of a cardiovascular event in a subject comprising the step of:administering a therapeutically effective amount of a compound offormula (I), a known colchicine derivative and/or a salt thereof.

Preferably, the subject has atherosclerotic vascular disease, morepreferably coronary disease, even more preferably clinically stablecoronary disease.

Therefore, the invention further provides a method for the prevention ortreatment of a cardiovascular event in a subject with atheroscleroticvascular disease comprising the step of: administering a therapeuticallyeffective amount of a compound of formula (I), a known colchicinederivative and/or a salt thereof.

The invention further provides a method for the prevention or treatmentof a cardiovascular event in a subject comprising the step of:administering a therapeutically effective amount of a compound offormula (I), a known colchicine derivative and/or a salt thereof,wherein the subject has a coronary disease prior to administration ofthe therapeutically effective amount of a compound of formula (I), aknown colchicine derivative and/or a salt thereof. Preferably thecoronary disease is a stable coronary disease.

The method may include the further step of co-administering a secondagent for the treatment and/or prevention of a cardiovascular event in asubject. For example, the composition delivered in the method mayfurther include an agent for anti-platelet therapy. Such anti-platelettherapy agents include: Irreversible cyclooxygenase inhibitors (such asAspirin); Adenosine diphosphate (ADP) receptor inhibitors (such asClopidogrel (Plavix®), Prasugrel (Effient®), Ticagrelor (Brilinta®),Ticlopidine (Ticlid®), Cangrelor); Phosphodiesterase inhibitors (such asCilostazol (Pletal®)); Glycoprotein IIB/IIIA inhibitors (such asAbciximab (ReoPro®), Eptifibatide (Integrilin®), Tirofiban(Aggrastat®)); Adenosine reuptake inhibitors (such as Dipyridamole(Persantine®)); Thromboxane inhibitors including Thromboxane synthaseinhibitors and Thromboxane receptor antagonists (such as Terutroban).

Additionally, the composition delivered in the method may include one ormore statins. Statins that may be used in the composition of the presentinvention include: simvastatin, atorvastatin, fluvastatin, lovastatin,pitavastatin, pravastatin, and rosuvastatin.

The additional statin and/or anti-platelet agent may be administered atthe same time as the compound of formula (I), a known colchicinederivative and/or a salt thereof, for example as tablets or capsulestaken at the same time as each other; within an hour of each other;within 2 hours, 4 hours, 6 hours, 8 hours or 12 hours of each other; orwithin a day of each other. Alternatively, the additional statin and/oranti-platelet agent may be in the same dosage form (for example the sametablet or capsule) as the compound of formula (I), a known colchicinederivative and/or a salt thereof.

The invention therefore provides a method for the prevention ortreatment of a cardiovascular event in a subject with atheroscleroticvascular disease comprising the step of: administering a therapeuticallyeffective amount of a compound of formula (I), a known colchicinederivative and/or a salt thereof and one or more additional agentsselected from the list comprising: a statin or an anti-platelet agent.

Preferably the atherosclerotic vascular disease is a coronary disease,which may be a clinically stable coronary disease or an unstablecoronary disease.

In one form of the invention, the methods comprise the administration ofa compound of formula (I).

In one form of the invention, the methods comprise the administration ofa compound selected from the group of compounds described in one or moreof the publications listed above as defining known colchicinederivatives.

In a preferred form of the invention, the compound of formula (I) hasone or more of the following features:

-   -   R₁, R₂, R₃, R₄, R₉, R₁₀, R₁₁ and R₁₂ independently represent        hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, halogen,        C₁₋₄ haloalkyl, nitro, amino, C₂₋₄ acylamino, hydroxyl, C₁₋₄        alkoxy, C₁₋₄ alkylthio, a group of the formula —SO₂N(R)₂ or        SO₂R^(x) where R^(x) is C₁-4 alky;    -   R₅′, R₅″, R₆′ and R₆″ independently represent hydrogen, C₁₋₄        alkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkyl,        nitro, amino, C₂₋₄ acylamino, hydroxyl, C₁₋₄ alkoxy or C₁₋₄        alkylthio a group of the formula —SO₂N(R^(x))₂ or SO₂R^(x) where        R^(x) is C₁₋₄ alkyl.

In a preferred form of the invention, the compound of formula (I) hasone or more of the following features:

-   -   a. At least one of R₁, R₂ and R₃ is C₁₋₄ alkoxy or C₁₋₄        alkylthio;    -   b. At least one of R₇ and R₈ is C₂₋₄ acyl;    -   c. R₁₀ is C₁₋₄ alkoxy or C₁₋₄ alkylthio

In a preferred form of the invention, the compound of formula (I) hastwo or more of the above-mentioned features.

In a preferred form of the invention, the compound of formula (I) haseach of the abovementioned features.

In a more preferred form of the invention, the compound of formula (I)has the following feature:

-   -   d. Each of R₄, R₅′, R₅″, R₆′, R₆″ R₁₁, R₁₂ is H.

In a more preferred form of the invention, the compound of formula (I)has the following feature:

-   -   e. one of R₇ and R₈ is H, and the other is C₂₋₄ acyl.

Thus, in a highly preferred form of the invention, the compound offormula (I) has each of the following features:

-   -   a. At least one of R₁, R₂ and R₃ is C₁₋₄ alkoxy or C₁₋₄        alkylthio;    -   b. At least one of R₇ and R₈ is C₂₋₄ acyl;    -   c. R₁₀ is C₁₋₄ alkoxy or C₁₋₄ alkylthio;    -   d. Each of R₄, R₄′, R₅″, R₆′, R₆″ R₁₁, R₁₂ is independently H;    -   e. One of R₇ and R₈ is H, and the other C₂₋₄ acyl.

Generally, C₁₋₄ alkoxy is preferred over C₁₋₄ alkylthio.

Generally, C₁₋₂ alkoxy is preferred over C₃₋₄ alkoxy.

In a preferred form of the invention, the compound of formula (I) isselected from the group of compounds defined by the following features:

-   -   R₁, R₂, R₃, and, R₁₀, R₁₁ independently represent C₁₋₄ alkoxy or        C₁₋₄ alkylthio;    -   R₇ and R₈ independently represent hydrogen or C₂₋₄ acyl; and    -   R₄, R₅′, R₅″, R₆′ and R₆″ independently represent hydrogen or        C₁₋₄ alkyl.

Preferably, R₁, R₂, R₃, and, R₁₀, R₁₁ independently represent C₁₋₄alkoxy.

Preferably still, each of R₁, R₂, R₃, and, R₁₀, R₁₁ represent C₁₋₄alkoxy.

Preferably R₄, R₅′, R₅″, R₆′ and R₆″ independently represent hydrogen.

Preferably still, each of R₄, R₅′, R₅″, R₆′ and R₆″ represent hydrogen.

In a highly preferred form of the invention, the compound of formula (I)has the following features:

-   -   each of R₁, R₂, R₃, and, R₁₀, R₁₁ represent C₁ alkoxy;    -   each of R4, R5′, R5″, R6′ and R6″ represent H;        R₇ represents H; and        R₈ represents C2 acyl;        such that the compound of formula (I) is colchicine.

Compounds of formula (I) of the invention are useful in both free baseor acid addition salt forms. The acid addition salts are preferably thepharmaceutically acceptable, non-toxic addition salts with suitableacids, such as those with inorganic acids, for example hydrochlorichydrobromic, nitric, sulfuric and phosphoric acids, or with organicacids, such as organic carboxylic acids, for example glycolic, maleic,hydroxymaleic, fumaric, malic, tartaric, citric, salicylic,o-acetoxybenzoic, nicotinic or isonicotinic acid, or organic sulfonicacids for example methanesulfonic, ethane sulfonic,2-hydroxyethanesulfonic, toluene-p-sulfonic or naphthalene-2-sulfonicacid.

Without wishing to be bound by any one theory, we believe the activityof a compound of formula (I), a known colchicine derivative and/or asalt thereof in relation to the prevention of vascular events inpatients with coronary disease may be due to the inhibition ofneutrophil function, leading to a reduction in the risk of plaqueinstability and thus the risk of de novo vascular events due todisruption of native atherosclerotic plaques in patients withatherosclerotic vascular disease such as coronary disease. For example,the colchicine may be preventing activation and amplification of the[cholesterol] crystal induced inflammation within atheroscleroticplaques and thereby acting to slow the progression of atherosclerosisand promote the stability of atherosclerotic plaques.

There is therefore provided a method for reducing or preventingcholesterol crystal induced inflammation within atherosclerotic plaquesin a subject, comprising the step of

-   -   administering a dosage of 0.5 mg or 0.6 mg of a compound of        formula (I), a known colchicine derivative and/or a salt        thereof.

Preferably the subject with atherosclerotic plaques has atheroscleroticvascular disease, more preferably a stable or unstable coronary disease.

Preferably the composition administered to reduce or prevent cholesterolcrystal induced inflammation within atherosclerotic plaques furthercomprises one or more additional agents selected from the listcomprising: a statin and/or an antiplatelet agent.

Preferably, the method of treatment of the present invention results inthe treatment or prevention of one or more of the followingcardiovascular events: acute coronary syndrome (including ischemic chestpain, acute myocardial infarction, unstable angina); cardiac arrest; orstroke such as non-cardio-embolic ischemic stroke.

Generally, the terms “treat”, “treating” and “treatment” and derivativesused herein have the meaning to affect a subject, tissue or cell toproduce a desired pharmacological and/or physiological effect. Thetreatment may be therapeutic in terms of: preventing progression of thecoronary disease or other atherosclerotic vascular disease andcardiovascular events; or causing a partial or complete cure and/orregression of the coronary disease or other atherosclerotic vasculardisease and cardiovascular events.

“Preventing” or “prevention” and derivative terms relate to the partialor complete prevention or at least delaying the onset of the developmentof coronary disease or other atherosclerotic vascular disease andcardiovascular events or the symptoms thereof in a subject who: has notyet been diagnosed with coronary disease or other atheroscleroticvascular disease or had a cardiovascular event; has had coronary diseaseand may be in remission and wishes to prevent re-occurrence of thecoronary disease and/or cardiovascular event; or has been diagnosed asbeing at risk of developing coronary disease or other atheroscleroticvascular disease and having a cardiovascular event.

The invention further provides for the use of a compound of formula (I),a known colchicine derivative and/or a salt thereof in the preparationof a medicament for the treatment or prevention of a cardiovascularevent.

The invention also provides for the use of a therapeutically effectiveamount of a compound of formula (I), a known colchicine derivativeand/or a salt thereof in the preparation of a medicament for theprevention or treatment of a cardiovascular event in a subject withatherosclerotic vascular disease.

Preferably the atherosclerotic vascular disease is a clinically stablecoronary disease or unstable coronary disease.

There is also provided the use of a therapeutically effective amount ofa compound of formula (I), a known colchicine derivative and/or a saltthereof in the preparation of a medicament for reducing or preventingcholesterol crystal induced inflammation within atherosclerotic plaquesin a subject.

The invention further provides for the use of a therapeuticallyeffective amount of a compound of formula (I) in the preparation of amedicament for the prevention or treatment of a cardiovascular event ina subject.

In another form of the invention, there is provided the use of atherapeutically effective amount of a compound selected from the groupof compounds described in one or more of the publications listed aboveas defining known colchicine derivatives in the preparation of amedicament for the prevention or treatment of a cardiovascular event ina subject.

Preferably, the medicament discussed above comprises between 0.01 and 1mg of a compound of formula (I), a known colchicine derivative and/or asalt thereof; between 0.05 and 0.95 mg, between 0.1 and 0.9 mg, between0.2 and 0.8 mg, or between 0.4 and 0.7 mg. More preferably, it comprisesbetween 0.5 mg and 0.6 mg of a compound of formula (I), a knowncolchicine derivative and/or a salt thereof, most preferably either 0.5mg or 0.6 mg.

The present invention further provides a composition for the preventionor treatment of a cardiovascular event in a subject, the compositioncomprising a therapeutically effective amount of a compound of formula(I), a known colchicine derivative and/or a salt thereof and one or morepharmaceutically acceptable additives, excipients carriers and/ordiluents.

The present invention further provides a composition for reducing orpreventing cholesterol crystal induced inflammation withinatherosclerotic plaques in a subject, the composition comprising atherapeutically effective amount of a compound of formula (I), a knowncolchicine derivative and/or a salt thereof and one or morepharmaceutically acceptable additives, excipients carriers and/ordiluents.

Preferably, the composition comprising a compound of formula (I), aknown colchicine derivative and/or a salt thereof comprises between 0.01and 1 mg of a compound of formula (I), a known colchicine derivativeand/or a salt thereof; between 0.05 and 0.95 mg, between 0.1 and 0.9 mg,between 0.2 and 0.8 mg, or between 0.4 and 0.7 mg. More preferably, itcomprises between 0.5 mg and 0.6 mg of a compound of formula (I), aknown colchicine derivative and/or a salt thereof, most preferablyeither 0.5 mg or 0.6 mg.

The exact amount of the a compound of formula (I), a known colchicinederivative and/or a salt thereof in the composition will of course,depend on the route of delivery, the nature of the coronary heartdisease or other atherosclerotic vascular disease, the therapeuticallyeffective amount of colchicine required and the general nature andhealth of the subject to whom the composition is delivered.

Preferably the concentration of the a compound of formula (I), a knowncolchicine derivative and/or a salt thereof in the composition will beof sufficient strength (qs) to provide a therapeutically effective doseto the target cells. Such therapy may be directed to the treatment orprevention of a cardiovascular event in a subject. More preferably, thetherapeutically effective dose is directed to the treatment orprevention of a cardiovascular event in a subject who hasatherosclerotic vascular disease such as stable or unstable coronarydisease.

The compositions of the present invention, comprising a compound offormula (I), a known colchicine derivative and/or a salt thereof, arepreferably adapted to be delivered to the subject in need more than oncedaily, once daily or less often. For example, if the composition isadapted for oral delivery, the composition is preferably administeredonce a day. However, it is contemplated that the composition can beadministered more frequently than this (for example, two or three timesa day) or less often (for example every second day, every third day,once a week). Alternatively, if the composition comprising a compound offormula (I), a known colchicine derivative and/or a salt thereof is inthe form of an injectable formulation, it is preferable that thecomposition be adapted for delivery once a week, or once a month.

The compositions may further comprise and one or more additional agentsselected from the list comprising: a statin and/or an anti-plateletagent.

As used herein, the term “therapeutically effective amount” means anamount of a compound of formula (I), a known colchicine derivativeand/or a salt thereof effective to yield a desired therapeutic response,for example to prevent or treat a cardiovascular event in a subject. Thespecific therapeutically effective amount will of course vary with suchfactors as the particular condition being treated, the physicalcondition and clinical history of the subject, the type of animal beingtreated, the duration of the treatment, the nature of concurrent therapy(if any), the specific formulations employed and the structure of thecomposition.

The term “pharmaceutically”, “physiologically”, or “veterinaryacceptable” as used herein refers to pharmaceutically active agents,physiologically active agents, veterinary active agents, or inertingredients which are suitable for use in oral formulations orformulations designed for contact with the skin of animals, includinghumans, without undue toxicity, incompatibility, instability,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio.

Additives, excipients carriers and diluents for use in the compositionsof the present invention include, without limitation: water, saline,ethanol, dextrose, glycerol, glycerol and polyhydric alcohols, milkprotein, vitamins, animal and vegetable oils, polyethylene glycols,lactose, dextrose, sucrose sorbitol, mannitol and other sugars,starches, gum acacia, calcium phosphates, alginate, tragacanth,gelatine, calcium silicate, cellulose and its derivatives such asmicrocrystalline cellulose and methyl cellulose, polyvinylpyrrolidone,water syrup, methyl and propylhydroxybenzoates, talc, magnesiumcarbonate, titanium dioxide, magnesium stearate and mineral oil orcombinations thereof.

The compositions can additionally include lubricating agents, dispersionmedia, pH buffering agents, wetting agents, emulsifying and suspendingagents, solvents, preserving agents, sweetening agents or flavouringagents, antifoaming agents, polymers, antioxidants, chelating agents,viscomodulators, tonicifiers, flavorants, colorants, odorants,opacifiers, suspending agents, binders, fillers, plasticizers,lubricants, absorption-promoting agents and mixtures thereof.Preservatives include antimicrobial, antibacterial and antifungalagents, antioxidants, chelating agents and inert gases. The particularselection of constituent that can be included in the compositionsdescribed herein will generally depend on the type of preparation.

In the preferred embodiments, the composition is formulated to enableready location and retention of the compound of formula (I), a knowncolchicine derivative and/or a salt thereof in the area required todeliver the therapeutic effect while at the same time not significantlyinterfering with the compound's efficacy. It will be understood,therefore, that the therapeutically effective composition may beformulated differently based on the area of treatment and how thecomposition is to be administered.

There are a range of reference sources for the development ofpharmaceutical compositions which may be referred to by the skilledperson when developing formulations comprising colchicine, such as“Remington's Pharmaceutical Sciences”, 21st Edition (2009), MackPublishing Company, Easton, Pa., USA, all the contents of which areincorporated herein.

A composition comprising a compound of formula (I), a known colchicinederivative and/or a salt thereof may be administered using standardprocedures, for example: orally, topically, parenterally,intraorbitally, ophthalmically, intraventricularly, intracranially,intracapsularly, intraspinally, intracisternally, intraperitoneally,buccally, rectally, vaginally, intranasally, or by aerosoladministration and/or inhalation spray or via an implanted reservoir.

In a preferred embodiment the compound of formula (I), a knowncolchicine derivative and/or a salt thereof is administered internallyfor the treatment or prevention of a cardiovascular event in a subject.For example, the compound may be delivered by oral routes in the form ofa tablet, capsule, liquid dose, gel or powder; by injection e.g. intothe blood stream, muscle tissue or directly into an organ such as theheart; by sublingual, buccal, rectal or intravaginal delivery; or byinhalation.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in oral, parenteral, sublingual, buccal, rectal or intravaginal orinhaled compositions may include: ion exchangers; alumina; aluminumstearate; lecithin; self-emulsifying drug delivery systems such asalpha-tocopherol polyethylene glycol 1000 succinate, or other similarpolymeric delivery matrices or systems such as nanoparticles; serumproteins such as human serum albumin; buffer substances such asphosphates; glycine; sorbic acid; potassium sorbate; partial glyceridemixtures of saturated vegetable fatty acids; water; salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts; colloidalsilica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-basedsubstances; polyethylene glycol; sodium carboxymethylcellulose;polyacrylates; polyethylene-polyoxypropylene-block polymers; and woolfat.

The composition of the present invention comprising a compound offormula (I), a known colchicine derivative and/or a salt thereof canfurther contain one or more additives, provided that they do notdetrimentally affect the therapeutic effect afforded by the compound offormula (I), a known colchicine derivative and/or a salt thereof. In oneembodiment, the additive is a colorant. In alternative embodiments, theadditive is a preservative such as a mould inhibitor or an anti-oxidant,a fragrance, or a stabiliser. The additional additives may also beagents that render the composition an emulsion, a micro-emulsion or anano-emulsion.

In a preferred embodiment, the compound of formula (I), a knowncolchicine derivative and/or a salt thereof is delivered via an oralroute. The colchicine may therefore be in the form of a tablet, capsule,gel or liquid composition. If the compound of formula (I), a knowncolchicine derivative and/or a salt thereof is in the form of a tablet,the tablet may further comprise fillers such as: lactose (milk sugar),microcrystalline cellulose, corn starch, sugars (including sucrose,mannitol, sorbitol, fructose, and dextrose), whey and yeast; and/orbinders such as: povidone, xanthan gum and Carbopol. Additionalingredients may be in the form of: disintergrants such as crospovidone,croscarmellose sodium, and gellan gum; coatings such as shellac;lubricants such as magnesium stearate, stearic acid, sodium stearylfumarate and hydrogenated vegetable oil; colorants such as titaniumdioxide and iron oxides; flavours (in chewable tablets); andplasticizers. Most preferably, the compound of formula (I), a knowncolchicine derivative and/or a salt thereof is administered in the formof a tablet comprising colchicine, magnesium stearate, lactose, maizestarch and povidone. Preferably, the tablet, capsule, gel or liquidcomposition comprises between 0.01 and 1 mg of a compound of formula(I), a known coichicine derivative and/or a salt thereof; between 0.05and 0.95 mg, between 0.1 and 0.9 mg, between 0.2 and 0.8 mg, or between0.4 and 0.7 mg. More preferably, it comprises between 0.5 mg and 0.6 mgof a compound of formula (I), a known coichicine derivative and/or asalt thereof, most preferably either 0.5 mg or 0.6 mg.

Alternatively, the compound of formula (I), a known coichicinederivative and/or a salt thereof may be delivered via sublingual,buccal, rectal or intravaginal delivery, for example by administrationof a tablet, capsule, gel, powder or spray.

In another embodiment, the compound of formula (I), a known colchicinederivative and/or a salt thereof is delivered parenterally, preferablyby injection, for example subcutaneously or intramuscularly. However,delivery may also be intra-arterially or intraperitoneally for thetreatment or prevention of a cardiovascular event in a subject. Thecomposition may be in the form of a sterile injectable preparation, forexample, as a sterile injectable suspension for the treatment orprevention of a cardiovascular event in a subject. This suspension maybe formulated according to techniques known in the art using suitabledispersing agents, surfactants, and suspending agents (e.g. Tween 80).The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent (e.g. 1, 2-propanediol). Acceptable vehicles and solvents mayinclude mannitol, water, Ringers solution and isotonic sodium chloridesolution with buffer. Furthermore, sterile, fixed oils may be employedas a solvent or a suspending medium. For this purpose, any bland fixedoil may be employed including mono- or diglycerides. Fatty acids, suchas oleic acid and its glyceride derivatives, and naturalpharmaceutically acceptable oils, such as polyoxyethylated olive oil orcastor oil, may also be used in the preparation of injectables.Preferably, the injectable composition comprises between 0.01 and 1 mgof a compound of formula (I), a known coichicine derivative and/or asalt thereof; between 0.05 and 0.95 mg, between 0.1 and 0.9 mg, between0.2 and 0.8 mg, or between 0.4 and 0.7 mg. More preferably, it comprisesbetween 0.5 mg and 0.6 mg of a compound of formula (I), a knowncolchicine derivative and/or a salt thereof, most preferably either 0.5mg or 0.6 mg.

The composition may further comprise a second agent for the treatmentand/or prevention of a cardiovascular event in a subject. For example,the composition may further include an agent for in anti-platelettherapy. Such antiplatelet therapy agents include: Irreversiblecyclooxygenase inhibitors (such as Aspirin); Adenosine diphosphate (ADP)receptor inhibitors (such as Clopidogrel (Plavix®), Prasugrel(Effient®), Ticagrelor (Brilinta®), Ticlopidine (Ticlid®), Cangrelor);Phosphodiesterase inhibitors (such as Cilostazol (Pletal®));Glycoprotein IIB/IIIA inhibitors (such as Abciximab (ReoPro®),Eptifibatide (Integrilin®), Tirofiban (Aggrastat®)); Adenosine reuptakeinhibitors (such as Dipyridamole (Persantine®)); Thromboxane inhibitorsincluding Thromboxane synthase inhibitors and Thromboxane receptorantagonists (such as Terutroban).

Additionally, the composition may include one or more statins. Statinsthat may be used in the composition of the present invention include:simvastatin, atorvastatin, fluvastatin, lovastatin, pitavastatin,pravastatin, and rosuvastatin.

The present invention also provides a regimen for the treatment orprevention of a cardiovascular event in a subject, the regimencomprising the step of:

-   -   administering a dosage of 0.5 mg or 0.6 mg of a compound of        formula (I), a known colchicine derivative and/or a salt thereof        once or more per day.

The present invention also provides a regimen for reducing or preventingcholesterol crystal induced inflammation within atherosclerotic plaquesin a subject, the regimen comprising the step of:

-   -   administering a dosage of 0.5 mg or 0.6 mg of a compound of        formula (I), a known colchicine derivative and/or a salt thereof        once or more per day.

Alternatively, the regimen may involve administering the compound offormula (I), a known colchicine derivative and/or a salt thereof everysecond day, every third day, every fourth day, every fifth day, everysixth day or once a week.

Preferably, the subject being administered the regimen hasatherosclerotic vascular disease, preferably a stable coronary disease.

The regimen may include the additional step of co-administering one ormore additional agents selected from the list comprising: a statinand/or an antiplatelet agent. The one or more additional agents may alsobe administered once per day.

Methods for synthesising compounds of formula (I) and/or knowncolchicine derivatives may be found in the following publications, thecontents of which are hereby incorporated by reference.

Substitution at R₁, R₂, R₃, R₄

1. Synthesis of Colchicine Derivatives Containing an Methoxyl:

-   Chang, Dong-Jo; Jung, Jong-Wha; An, Hongchan; Suh, Young-Ger; Yoon,    Eun-Young; Lee, Geon-Bong; Kim, Soon-Ok; Kim, Wan-Joo; Kim,    Young-Myeon, Design, synthesis and identification of novel    colchicine-derived immunosuppressant, Bioorganic and Medicinal    Chemistry Letters; vol. 19; nb. 15; (2009); p. 4416-4420.-   Hufford, Charles D.; Capraro, Hans-Georg; Brossi, Arnold. (13)C- and    (1)H-NMR. Assignments for Colchicine Derivatives, Helvetica Chimica    Acta; Vol. 63(1); (1980); p. 50-56.

2. Synthesis of Colchicine Derivatives Having Substituent at R₄:

-   Bensel, Nicolas; Lagnoux, David; Niggli, Verena; Wartmann, Markus;    Reymond, Jean-Louis New C(4)-Functionalized Colchicine Derivatives    by a Versatile Multicomponent Electrophilic Aromatic Substitution    Helvetica Chimica Acta; Vol. 87(9); (2004); p. 2266-2272.

3. Synthesis of Colchicine Derivative Containing a Containing an AcetylFunctional Group at R₄:

-   Kouroupis, Pavlos; Linden, Anthony; Hansen, Hans-Juergen, Synthesis    of 4-Acetylcolchicine Helvetica, Chimica Acta; Vol. 79, (1996); p.    203-207:    Substitution at R₈ or R₇

1. Synthesis of Colchicine Derivatives Containing an Azide Group:

-   Malysheva, Yulia B.; Fedorov, Alexey Yu.; Combes, Sebastien;    Allegro, Diane; Peyrot, Vincent; Knochel, Paul; Gavryushin, Andrei    E., Synthesis and biological evaluation of novel anticancer bivalent    colchicine-tubulizine hybrids Bioorganic and Medicinal Chemistry;    Vol. 20(14); (2012); p. 4271-4278.

2. Synthesis of Colchicine Derivatives Containing an Amide Group:

-   Bensel, Nicolas; Lagnoux, David; Niggli, Verena; Wartmann, Markus;    Raymond, Jean-Louis New C(4)-Functionalized Colchicine Derivatives    by a Versatile Multicomponent Electrophilic Aromatic Substitution    Helvetica Chimica Acta; Vol. 87(9); (2004); p. 2266-2272

Substitution at R₁₀

1. Synthesis of Colchicine Derivative Containing a Thio Group.

-   Kozaka, Takashi; Nakagawa-Goto, Kyoko; Shi, Qian; Lai, Chin-Yu;    Brossi, Arnold; Lee, Kuo-Hsiung; Hamel, Ernest; Bastow, Kenneth F.,    Antitumor agents 273. Design and synthesis of    N-alkyl-thiocolchicinoids as potential antitumor agents, Bioorganic    and Medicinal Chemistry Letters; vol. 20(14); (2010); p. 4091-4094.-   Danieli, Bruno; Giardini, Alessandra; Lesma, Giordano; Passarella,    Daniele; Peretto, Bruno; Sacchetti, Alessandro; Silvani, Alessandra;    Pratesi, Graziella; Zunino, Franco, Thiocolchicine-Podophyllotoxin    Conjugates: Dynamic Libraries Based on Disulfide Exchange Reaction,    Journal of Organic Chemistry; Vol. 71: 7; (2006); p. 2848-2853.-   Quinn, Frank R.; Neiman, Zohar; Beisler, John A. Toxicity    Quantitative Structure—Activity Relationships of Colchicines Journal    of Medicinal Chemistry; Vol. 24(5); (1981); p. 636-639

2. Synthesis of Colchicine Derivative Containing an Haloalkyl FunctionalGroup.

-   Chang, Dong-Jo; Jung, Jong-Wha; An, Hongchan; Suh, Young-Ger; Yoon,    Eun-Young; Lee, Geon-Bong; Kim, Soon-Ok; Kim, Wan-Joo; Kim,    Young-Myeon, Design, synthesis and identification of novel    colchicine-derived immunosuppressant, Bioorganic and Medicinal    Chemistry Letters; Vol. 19(15); (2009); p. 4416-4420.

3. Synthesis of Colchicine Derivative Containing an Alkoxy Group.

-   Kouroupis, Pavlos; Kessler, Jacqueline; Hansen, Hans-Juergen,    10-Alkyl-10-demethylcolchicines, Helvetica Chimica Acta; Vol. 79;    (1996); p. 208-212.

4. Synthesis of Colchicine Derivative Containing an Hydroxyl Group.

-   Kouroupis, Pavlos; Hansen, Hans-Jurgen, From Colchicine and Some of    Its Derivatives to 1,2,3,9,10-Pentamethoxybenzo[a]heptalenes,    Helvetica Chimica Acta; Vol. 78; (1995); p. 1247-1277.-   Sun, Li; McPhail, Andrew T.; Hamel, Ernest; Lin, Chii M.; Hastie,    Susan B.; et al. Antitumor Agents. 139. Synthesis and Biological    Evaluation of Thiocolchicine Analogs 5,6-Dihydro-6(S)-(acyloxy)- and    5,6-Dihydro-6(S)-(aroyloxy)methyl-1,2,3-trimethoxy-9-(methylthio)-8H-cyclohepta[a]naphthalen-8-ones    as Novel Cytotoxic and Antimitotic Agents, Journal of Medicinal    Chemistry; Vol. 36(5); (1993); p. 544-551.

EXAMPLES

The following examples are provided to further illustrate severalembodiments of the invention.

Example 1

A prospective randomized observer blinded end-point trial was conductedto determine whether adding 0.5 mg/day of colchicine to standardsecondary prevention therapies including aspirin and high dose statinsreduces the risk of cardiovascular events in patients with objectivelydiagnosed and clinically stable coronary disease.

Methods

Study Conduct and Design: The LoDoCo Trial was conducted under theauspices of the Heart Research Institute of Western Australia. It wasdesigned by the principal investigators, registered with the AustralianClinical Trial Registry [12610000293066], and received ethics approvalfrom the Human Research Ethics Committee at Sir Charles GairdnerHospital Perth Western Australia in July 2008. There was no externalfunding source.

We employed a PROBE [Prospective Randomized, Open, Blinded End-point]design [8] Eligible consenting patients with established coronarydisease presenting for routine clinical review were randomized toreceive colchicine 0.5 mg/day or no colchicine without any other changeto their medical therapy. All outcomes were evaluated by an experiencedadjudicator blinded to the treatment allocation.

Study Size and Eligibility: It was planned to recruit a study populationthat would include 250 patients randomized to the control group and 250patients randomized to treatment who were tolerant of colchicine for atleast 4 weeks after the date of their randomization.

Patients were eligible for inclusion if they met each of the followingcriteria: 1] angiographically proven coronary disease; 2] aged 35 to 85years; 3] clinically stable for at least 6 months, 4] no major competingco-morbidities or contra-indication to colchicine therapy, 5] consideredto be compliant with therapy and attending routine cardiology follow upappointments, and 6] willing to be consented and randomized into thestudy. Patients with a history of bypass surgery were only eligible ifthey had undergone bypass surgery more than 10 years before, or hadangiographic evidence of graft failure or had undergone stenting sincetheir bypass surgery. All patients signed informed consent beforerandomization.

Randomization: The randomization sequence was computer generated, keptconcealed from the investigators at all times and was managed by aresearch assistant who had no involvement in the evaluation ormanagement of study patients. Once the assistant received the consentform, the patients' demographic data were entered into the data base andthe investigators and patients were advised in writing of the treatmentgroup to which the patient had been assigned.

Despite electing to use the lowest dose of colchicine available, it wasanticipated that a number of patients would withdraw from therapy earlyafter randomization due to gastrointestinal side effects. In order toensure that the requisite number of patients in the treatment arm wereactually tolerant of treatment, the protocol allowed for the researchassistant to assign a newly recruited patient to treatment if a patientdiscontinued colchicine due to side effects in the first month. Patientswho were intolerant to therapy remained in the study, and were followedin the usual manner and included in the primary intention to treatanalysis.

Intervention: Patients randomized to active treatment were given aprescription for colchicine 0.5 mg daily by their referringcardiologist. The drug was dispensed by their usual chemist, and ifrequested, patients were reimbursed for the cost of these scripts. Allother treatments were continued as usual.

Follow-up and definition of clinical outcomes: Patient compliance withtreatment and outcome data were collected at routine follow up visitsand at the time of any unplanned hospital admission.

An acute coronary syndrome (ACS) was defined as either [a] AcuteMyocardial Infarction (AMI), as evidenced by acute ischemic chest painassociated with a rise in serum troponin above the upper limit of normal[9] or [b] Unstable Angina (UA), as evidenced by a recent accelerationof the patients angina unassociated with a rise in serum troponin butassociated with angiographic evidence of a change in the patient'scoronary anatomy. (Unstable Angina Braunwald classification types IB andIIB) [10]. The ACS was characterized as being stent-related if there wasevidence of significant in-stent stenosis or acute stent thrombosis. Outof Hospital Cardiac Arrest was defined as either a sudden death asevidenced on the patients' death certificate, or a non-fatal out ofhospital cardiac arrest, defined as a recovery from sudden collapseassociated with documented asystole, ventricular tachycardia orventricular fibrillation. Noncardio-embolic ischemic stroke was definedas CT or MRI proven ischemic stroke adjudged by the treating neurologistas not being due to atrial fibrillation or intracranial hemorrhage.

The primary efficacy outcome was the composite, ACS, fatal or non-fatalout of hospital cardiac arrest or non-cardio-embolic ischemic stroke.

Secondary outcomes were [a] individual components of the primaryoutcome, and [b] the components of ACS unrelated to stent disease.

Timelines: The pre-specified study duration was a minimum follow up oftwo years in all patients. Accordingly the study was closed on May 31,2012. During May, all living patients were contacted by phone to collectcompliance and outcome data from the last date of follow-up. Finaloutcome data were available in all patients and no patients were lost tofollow up.

Statistical Power: Assuming that the control group had a combined eventrate [ACS, out of hospital cardiac arrest or non cardio-embolic-ischemicstroke] of 8% [11], an accrual interval of 2 years and a follow-up afterthe accrual interval of 2 years, the planned sample size provided >80%power to detect a hazard ratio of <0.50 based on a two sidedsignificance level of 5%.

Data analysis: Summary statistics, including mean and standard deviationwere calculated for all baseline characteristics by treatment arm. Alltime to event outcomes were calculated in days by subtracting the dateof randomization from either: (1) the date of event or death; or (2) thetrial termination date for those patients not experiencing the definedevent.

As pre-specified, the primary efficacy analysis was based on theintention-to-treat principle. The intention-to-treat analysis includedall randomized subjects and all events during the time fromrandomization to the trial termination. Trial termination date was fixedas May 31, 2012. A secondary pre-specified on treatment analysis wasalso performed, based on patients who were both tolerant and compliantto therapy beyond the first month of randomization. All events duringthe time from randomisation until non-compliance with colchicinetreatment regimen were included in this analysis.

The time-to-first-event for all outcomes is presented using aKaplan-Meier plot.

The primary efficacy outcome was analysed using a cox proportionalhazards model including treatment group coded as control or colchicine.The secondary outcomes were analysed similarly. In addition, the primaryanalysis was stratified by gender, age, diagnosis of diabetes, pastmyocardial infarction, unstable angina, coronary bypass surgery,coronary angioplasty, and therapy with aspirin, clopidogrel or both,high dose statin therapy (defined as a dose of statin equivalent toatorvastatin of 40 mg or more), beta blockers, calcium blockers and ACEinhibitors.

Results

Study Population: Between August 2008 and May 2010, 901 patients withstable coronary disease attending for routine out-patient cardiologyreview were assessed for eligibility for the study. Of these, 297 [33%]did not meet the entry criteria, 72 [8%] declined to participate and 532[59%] were enrolled into the study, 250 of whom were randomized to thecontrol group and 282 to treatment. Of those randomized to treatment 32[11%] reported early intolerance, due to gastrointestinal side effects,and 7 patients subsequently reported that they chose not start therapy(FIG. 1). All 532 randomized patients were followed for the duration ofthe study period which ranged from a minimum of 24 to a maximum of 44months. Median follow up was 36 months.

Baseline characteristics according to ‘randomized treatment groups areshown in Table. 1. Both groups were well matched for important clinicalcharacteristics although more patients in the colchicine group weretaking calcium channel blockers and less were taking beta-blockertherapy. Almost all patients in each group were taking anti-platelettherapy and high dose statin therapy.

TABLE 1 Study Population Control n [%] Treatment n [%] Total 250 282Mean Age 67 ± 9.2 66 ± 9.6 Males 222 [89] 251 [89] Diabetic  69 [28]  92[33] Smoker  14 [6]  10 [4] Past AMI or UA  61 [24]  64 [23] CABG  39[16]  62 [22] PTCA 138 [55] 169 [60] Aspirin and/or Plavix 235 [94] 262[93] DAPT  24 [10]  38 [13] High Dose Statins 235 [94] 271 [96] BB¹ 178[71] 176 [62] CBB²  25 [10]  52 [18] ACE 150 [60] 155 [55] ¹p < 0.05 ²p< 0.01 for the comparison of the distributions between treatment andcontrol Past AMI or UA History of myocardial infarction or unstableangina CABG Coronary Artery Bypass Surgery PTCA History of PercutaneousCoronary Angioplasty DAPT Dual anti-platelet therapy [Aspirin andClopidogrel] BB Beta-blocker therapy, CCB Calcium Chanel Blocker therapyACE ACE inhibitor therapy

Late discontinuations: 30 patients ceased colchicine therapy after amean period of 2.36 years. Therapy was ceased due to an unrelatedinter-current illness in 11 patients, by choice in 5, and for a varietyof possible drug related effects in 14 patients [4.9%] as described inTable 2.

TABLE 2 Withdrawals from therapy n [%] Early Withdrawals 32 [11] LateWithdrawals* 30 [11] Unrelated inter-current illness 11 [3.9] PatientChoice  5 [1.8] Perceived Side effects Intestinal upset  7 [2.5] Myalgia 2 [0.90] Myositis  1 [<0.5] Rash  1 [<0.5] Alopecia  1 [<0.5] Itch  1[<0.5] Peripheral Neuritis  1 [<0.5] *Withdrawals after 30 days, Averagetime to withdrawal 2.36 years

Outcomes; A primary outcome occurred in 55/532 patients, including15/282 [5.3%] patients assigned to colchicine treatment, and 40/250[16%] patients assigned to the control group [hazard ratio 0.33, 95% CI;0.18-0.59; p<0.001, number needed to treat 11]. A sensitivity analysiswas performed for the primary outcome, adjusting for the usage ofcalcium channel blockers and beta blocker therapy. These results wereconsistent with the primary analysis.

The time to first clinical event in each group by treatment is shown inFIG. 2. The effect of colchicine on the primary outcome was evidentearly and the benefits of colchicine continued to accrue throughout thefollow up period. Results of the primary analysis were consistent in allsubgroups examined (FIG. 3); There was no evidence of differentialtreatment effects based on any of the clinical or therapeutic variables.

The reduction in the primary outcome was largely driven by the reductionin the number of patients presenting with an ACS, [13/282 [4.6%] vs34/250 [13.4%], hazard ratio 0.33; 95% CI; 0.18-0.63; p<0.001]. Out ofhospital cardiac arrest and non-cardio-embolic ischemic stroke wereinfrequent but were also reduced in the treatment group (Table 3).

TABLE 3 Primary Outcome and its Components Control Treatment [n = 250][n = 282] n [%] n [%] HR 95% CI p value Primary Outcome 40 [16] 15 [5.3]0.33; 0.18-0.59 <0.001 Components of Primary Outcome Acute Coronary 34[13.6] 13 [4.6] 0.33; 0.18-0.63 <0.001 Syndrome OOH Cardiac Arrest  2[0.8]  1 [0.35]¹ 0.47; 0.04-5.15 0.534 Non-Cardio-Embolic  4 [1.6]  1[0.35] 0.23; 0.03-2.03 0.184 Stroke Components of ACS Stent Related  4[1.6]  4 [1.4] NS Non-Stent Related 30 [12]  9 [3.2] 0.26; 0.12-0.55<0.001 Non-Stent Related AMI 14 [5.6]  4 [1.6] 0.25; 0.08-0.76 0.014Non-Stent Related UA 16 [12]  5 [2.4] 0.27; 0.10-0.75 0.011 OOH Out ofHospital ACS Acute Coronary Syndrome AMI Acute Myocardial Infarction UAUnstable Angina ¹Non-Fatal

Of the 47 patients who presented with an ACS, the event was stentrelated in 8 [17%] [2 in each group had evidence of acute stentthrombosis and 2 in each group had evidence of significant in-stentstenosis]. Further analysis confirmed that patients randomized totreatment were less likely to present with an ACS unrelated to stentdisease (9/282 [3.2%] vs 30/250 [12%] hazard ratio 0.26, 95% CI;0.12-0.55; p<0.001), be it associated with an AMI (4/282 [1.4%] vs14/250 [5.6%] hazard ratio 0.25, 95% CI; 0.08-0.76; p=0.014) or UA(5/282 [1.8%] vs 16/250 [6.4%] hazard ratio 0.27, 95% CI; 0.10-0.75;p=0.011). (FIG. 4, Table 3)

Of 39 patients randomized to treatment who did not receive therapybeyond the first month due to early intolerance or non-compliance, 4[10%] presented with an ACS due to acute stent thrombosis (n=1) and UA(n=3). Patients who were both compliant and tolerant to therapy beyondthe first month of randomization had significantly fewer events than thecontrol patients (11/243 [4.5%] vs 40/250 [16%] hazard ratio 0.29, 95%CI; 0.15-0.56; p<0.001). The results of all on-treatment analyses wereconsistent with those based upon the intention to treat analyses (Table4).

TABLE 4 Primary Outcome and its Components [On-Treatment Analysis]Control Treatment [n = 250] [n = 243] n [%] n [%] HR; 95% CI p-valuePrimary Outcome 40 [16] 11 [5.3] 0.29 (0.15, 0.56) <0.001 Components ofPrimary Outcome Acute Coronary 34 [13.6]  9 [4.6] 0.28 (0.13, 0.58)<0.001 Syndrome OOH Cardiac Arrest  2 [0.8]  1 [0.35]¹ 0.55 (0.05, 6.03)0.622 Non-Cardio-Embolic  4 [1.6]  1 [0.35] 0.27 (0.03, 2.42) 0.242Stroke Components of ACS Stent Related  4 [1.6]  3 [1.4] NS Non-StentRelated 30 [12]  6 [3.2] 0.21 (0.09, 0.50) <0.001 Non-Stent Related 14[5.6]  4 [1.6] 0.30 (0.10, 0.91) 0.033 AMI Non-Stent Related 16 [12]  2[2.4] 0.13 (0.03, 0.57) 0.007 UA OOH Out of Hospital ACS Acute CoronarySyndrome AMI Acute Myocardial Infarction UA Unstable Angina ¹Non-Fatal

Ten patients in the control group died compared with 4 patients in thecolchicine group. Of the 10 controls, 5 died of presumed cardiac cause;2 following an out-of-hospital cardiac arrest, 2 from cardiogenic shockfollowing myocardial infarction, and 1 following bypass surgery. All 4patients in the colchicine group died of non-cardiac causes.

The LoDoCo trial demonstrates that the addition of colchicine 0.5 mg/dayto standard therapy in patients with stable coronary diseasesignificantly reduces the risk of a cardiovascular event, including anACS, out of hospital cardiac arrest and non-cardio-embolic ischemicstroke. The benefits of colchicine were achieved on a background ofwidespread use of effective secondary prevention strategies, includinghigh dose statins, as evidenced by the low event rate in the controlgroup. The effect of adding colchicine became evident early, continuedto accrue over time and was largely driven by a reduction in ACSunrelated to stent disease.

Numerous variations and modifications will suggest themselves to personsskilled in the relevant art, in addition to those already described,without departing from the basic inventive concepts. All such variationsand modifications are to be considered within the scope of the presentinvention, the nature of which is to be determined from the foregoingdescription.

1. A method for treating and/or reducing the risk of a cardiovascularevent in a subject in need thereof, which comprises: administering tothe subject a therapeutically effective amount of a compositioncomprising about 0.5 total mg of (i) colchicine, (ii) a salt of (i), orany combination of (i) and (ii), wherein the composition is administeredorally and once per day.
 2. The method of claim 1, wherein thecomposition is administered in the form of a tablet or capsule.
 3. Themethod of claim 1, wherein the composition is administered in the formof a liquid dose, gel, or powder.
 4. The method of claim 1, wherein thesubject has atherosclerotic vascular disease.
 5. The method of claim 4,wherein the atherosclerotic vascular disease is coronary disease.
 6. Themethod of claim 1, wherein the composition reduces the risk of thesubject experiencing a cardiovascular event by a greater percentage thana composition that does not include colchicine or a salt thereof, andwherein the risk of cardiovascular event is reduced by at least about10%, at least about 20%, at least about 30%, at least about 40%, or atleast about 50%.
 7. The method of claim 6, wherein the risk ofcardiovascular event is reduced by at least about 30%.
 8. The method ofclaim 1, wherein the subject has a previous diagnosis of diabetes, pastmyocardial infarction, unstable angina, coronary bypass surgery, and/orcoronary angioplasty.
 9. The method of claim 1, wherein the subject isfrom about 35 to about 85 years of age.
 10. The method of claim 1,wherein the cardiovascular event is acute coronary syndrome.
 11. Themethod of claim 10, wherein the acute coronary syndrome is unstableangina.
 13. The method of claim 10, wherein the acute coronary syndromeis ischemic chest pain, acute myocardial infarction, and/or unstableangina.
 14. The method of claim 10, wherein the acute coronary syndromeis acute myocardial infarction.
 15. The method of claim 1, wherein thecardiovascular event is cardiac arrest.
 16. The method of claim 1,wherein the cardiovascular event is stroke.
 17. The method of claim 10,wherein the acute coronary syndrome is due to stent disease or acutestent thrombosis.
 18. The method of claim 14, wherein the acutemyocardial infarction is non-stent related acute myocardial infarction.19. The method of claim 1, wherein the subject is administered thecomposition daily for at least 24 months.
 20. The method of claim 1,wherein the subject is administered the composition daily for at least36 months.
 21. The method of claim 1, wherein the subject isadministered the composition daily for at least 44 months.